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Abstract
Gating pore currents through the voltage-sensing domains (VSDs) of the skeletal muscle voltage-gated sodium channel NaV1.4 underlie hypokalemic periodic paralysis (HypoPP) type 2. Gating modifier toxins target ion channels by modifying the function of the VSDs. We tested the hypothesis that these toxins could function as blockers of the pathogenic gating pore currents. We report that a crab spider toxin Hm-3 from Heriaeus melloteei can inhibit gating pore currents due to mutations affecting the second arginine residue in the S4 helix of VSD-I that we have found in patients with HypoPP and describe here. NMR studies show that Hm-3 partitions into micelles through a hydrophobic cluster formed by aromatic residues and reveal complex formation with VSD-I through electrostatic and hydrophobic interactions with the S3b helix and the S3-S4 extracellular loop. Our data identify VSD-I as a specific binding site for neurotoxins on sodium channels. Gating modifier toxins may constitute useful hits for the treatment of HypoPP.
Keywords
hypokalemic periodic paralysis, channelopathy, sodium channel, neurotoxin, gating modifier, GATED SODIUM-CHANNELS, VOLTAGE-SENSOR MUTATIONS, TARANTULA TOXIN, ENHANCED INACTIVATION, HERIAEUS-MELLOTEEI, ION CHANNELS, MUSCLE, CHANNELOPATHIES, PATHOPHYSIOLOGY, DEPOLARIZATION

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Chicago
Männikkö, Roope, Zakhar O Shenkarev, Michael G Thor, Antonina A Berkut, Mikhail Yu Myshkin, Alexander S Paramonov, Dmitrii S Kulbatskii, et al. 2018. “Spider Toxin Inhibits Gating Pore Currents Underlying Periodic Paralysis.” Proceedings of the National Academy of Sciences of the United States of America 115 (17): 4495–4500.
APA
Männikkö, Roope, Shenkarev, Z. O., Thor, M. G., Berkut, A. A., Myshkin, M. Y., Paramonov, A. S., Kulbatskii, D. S., et al. (2018). Spider toxin inhibits gating pore currents underlying periodic paralysis. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 115(17), 4495–4500.
Vancouver
1.
Männikkö R, Shenkarev ZO, Thor MG, Berkut AA, Myshkin MY, Paramonov AS, et al. Spider toxin inhibits gating pore currents underlying periodic paralysis. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA. 2018;115(17):4495–500.
MLA
Männikkö, Roope, Zakhar O Shenkarev, Michael G Thor, et al. “Spider Toxin Inhibits Gating Pore Currents Underlying Periodic Paralysis.” PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 115.17 (2018): 4495–4500. Print.
@article{8584497,
  abstract     = {Gating pore currents through the voltage-sensing domains (VSDs) of the skeletal muscle voltage-gated sodium channel NaV1.4 underlie hypokalemic periodic paralysis (HypoPP) type 2. Gating modifier toxins target ion channels by modifying the function of the VSDs. We tested the hypothesis that these toxins could function as blockers of the pathogenic gating pore currents. We report that a crab spider toxin Hm-3 from Heriaeus melloteei can inhibit gating pore currents due to mutations affecting the second arginine residue in the S4 helix of VSD-I that we have found in patients with HypoPP and describe here. NMR studies show that Hm-3 partitions into micelles through a hydrophobic cluster formed by aromatic residues and reveal complex formation with VSD-I through electrostatic and hydrophobic interactions with the S3b helix and the S3-S4 extracellular loop. Our data identify VSD-I as a specific binding site for neurotoxins on sodium channels. Gating modifier toxins may constitute useful hits for the treatment of HypoPP.},
  author       = {M{\"a}nnikk{\"o}, Roope and Shenkarev, Zakhar O and Thor, Michael G and Berkut, Antonina A and Myshkin, Mikhail Yu and Paramonov, Alexander S and Kulbatskii, Dmitrii S and Kuzmin, Dmitry A and Sampedro Casta{\~n}eda, Marisol and King, Louise and Wilson, Emma R and Lyukmanova, Ekaterina N and Kirpichnikov, Mikhail P and Schorge, Stephanie and Bosmans, Frank and Hanna, Michael G and Kullmann, Dimitri M and Vassilevski, Alexander A},
  issn         = {0027-8424},
  journal      = {PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA},
  language     = {eng},
  number       = {17},
  pages        = {4495--4500},
  title        = {Spider toxin inhibits gating pore currents underlying periodic paralysis},
  url          = {http://dx.doi.org/10.1073/pnas.1720185115},
  volume       = {115},
  year         = {2018},
}

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